A combination of ternary classification models and reporter gene assays for the comprehensive thyroid hormone disruption profiles of 209 polychlorinated biphenyls

Abstract Computational toxicology is widely applied to screen tens and thousands of potential environmental endocrine disruptors (EDCs) for its great efficiency and rapid evaluation in recent years. Polychlorinated biphenyls (PCBs) with 209 congeners have not been comprehensively tested for their ability to interact with the thyroid receptor (TR), which is one of the most extensively studied targets related to the effects of EDCs. In this study, we aimed to determine the thyroid-disrupting mechanisms of 209 PCBs through the combination of a novel computational ternary classification model and luciferase reporter gene assay. The reporter gene assay was performed to examine the hormone activities of 22 PCBs via TR to classify their profiles as agonistic, antagonistic or inactive. Thus, six agonists, eleven antagonists and seven inactive chemicals against TR were identified in in vitro assays. Then, six relevant variables, including molecular structural descriptors and molecular docking scores, were selected for describing compounds. Machine learning methods (i.e., linear discriminant analysis (LDA) and support vector machines (SVM)) were used to build classification models. The optimal model was obtained by using SVM, with an accuracy of 88.24% in the training set, 80.0% in the test set and 75.0% in 10-fold cross-validation. The remaining 187 PCB congeners' hormone activities were predicted using the obtained models. Out of these PCBs, the SVM model predicted 38 agonists and 81 antagonists. The findings revealed that higher chlorinated PCBs tended to have TR-antagonistic activities, whereas lower chlorinated PCBs were agonists. This study provided a reference for further exploring PCBs' thyroid effect.